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Experts Question Cochrane Review of Hepatitis C DAA Treatment


A systematic review of hepatitis C direct-acting antiviral (DAA) studies published by the Cochrane Collaboration has been strongly criticized by doctors and advocates for its conclusion that there is no evidence that the expensive drugs prolong life or reduce liver-related disease in people who achieve a sustained virological response to treatment -- a cure, in current understanding.

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Systematic reviews have become highly influential in health policy-making and the development of clinical guidelines. The reviewers carry out a systematic search for all published and unpublished scientific studies relevant to a scientific question, rate the quality of those studies, and calculate the overall effect of an intervention or treatment. In particular, systematic reviews seek to minimize bias caused by poor study design, inadequate follow-up, or incomplete publication of results. The Cochrane Collaboration has published numerous systematic reviews in all areas of medicine and its reviews are highly regarded.

The Cochrane Collaboration’s review of the impact of DAAs on mortality, morbidity, and serious adverse events identified 138 randomized trials with a total of 25,232 participants; 57 of the trials looked at products that have either been discontinued in development or withdrawn from the market. The average follow-up period was 34 weeks.

Only 11 studies comprising follow-up on 2996 people reported on mortality and morbidity; meta-analysis of these studies found no significant difference in outcomes in people who received DAAs or placebo. A grand total of 16 deaths were reported in these studies and the median follow-up time in these studies is not stated for this analysis.

The study also found no impact of DAAs by subgroups such as people with cirrhosis or chronic kidney disease, by hepatitis C virus (HCV) genotype, treatment history, or interferon or ribavirin usage.

The review also looked at serious adverse events -- both drug side effects and other serious events such as liver decompensation -- and found that in 43 studies, comprising follow-up on 15,587 people, there was no difference in the rate of serious adverse events between those who received DAAs and those who did not.


The Cochrane reviewers highlight a major limitation of their review: most trials had short follow-up periods, so "our results can neither confirm nor reject that DAAs have clinical long-term effects." In fact, the average follow-up period of just 34 weeks was far too short to detect any effect on mortality except in people with decompensated cirrhosis and end-stage liver disease.

In a letter to The Guardian, Graham Foster of Queen Mary University of London and senior colleagues from the U.K. said: "The trials were neither designed, nor powered, to assess mortality, so it is not at all surprising that the Cochrane review was unable to identify any impact on mortality."

In contrast, a systematic review of 31 studies of the effect of pegylated interferon and ribavirin on the survival of people after being cured of hepatitis C was able to draw on studies that followed people for a median of 5.4 years, allowing researchers from Imperial College London to conclude that a sustained virological response to treatment reduced the risk of death by 50% to 80% over 5 years.

Another weakness of the Cochrane review was the lack of deaths during the follow-up period: 16, compared to 2210 in the studies of pegylated interferon and ribavirin-treated people reviewed by the researchers from Imperial College.

The authors of the review also described the well-accepted relationship between sustained virological response and long-term outcomes of liver disease as a "non-validated surrogate outcome."

"I'm not sure how the Cochrane Collaboration could claim that curing hepatitis C with new direct-acting antiviral drugs does not improve survival," commented Andrew Hill, one of the authors of the Imperial College review.

"They could claim that being cured of hepatitis C with the new drugs is somehow different in terms of survival, compared to being cured on the old interferon-based treatments. But this would be hard to understand -- for most experts, curing hepatitis C should have the same clinical consequences, no matter what treatment is used to achieve this."

The review does identify the lack of independent, long-term follow-up of people treated with DAAs as a problem. Almost all studies were classified as low-quality evidence, mainly due to pharmaceutical company sponsorship and design, and because of technical problems in the way that procedures such as randomization were carried out.

"As a patient-led and patient-driven organization, we have seen, heard, and experienced the real evidence of being treated with DAAs. The true story is one of remarkable, if surprising, success over just a decade, transforming an unpleasant and sometimes fatal disease into one that is readily cured," said Charles Gore, President of the World Hepatitis Alliance. "What is absolutely imperative is that this Review should not be used as another excuse not to treat when currently only 1.5% of people living with hepatitis C are accessing treatment worldwide."



JC Jakobsen et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database of Systematic Reviews. Issue 6, No. CD012143. June 6, 2017.